Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat on adenine-induced renal injury

Abstract

The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model.

Utility of urinary tubular markers for monitoring chronic tubulointerstitial injury after ischemia–reperfusion

“…Tissues fixed in methyl Carnoy's solution (60% methanol, 30% chloroform, and 10% glacial acetic acid) were embedded in paraffin. Serial sections (2‐μm thickness) were prepared for conventional histological assessment of Masson's trichrome staining, and for immunohistochemistry, and an indirect immunoperoxidase method was used to detect target antigens, as described previously …”

“…Serial sections (2-μm thickness) were prepared for conventional histological assessment of Masson's trichrome staining, and for immunohistochemistry, and an indirect immunoperoxidase method was used to detect target antigens, as described previously. 17,20 Tissue fibrosis was defined as accumulation of extracellular matrix shown in blue in Masson's trichrome staining assessed at under ×100 magnification. Ten nonoverlapping fields from cortical and outer medullary areas were selected.…”

Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats

“…Previous studies demonstrated that topiroxostat reduced urinary albumin excretion in adenine‐induced kidney injury mice and in diabetic db/db mice (Kamijo‐Ikemori et al. ; Nakamura et al. ).…”

Renoprotective effects of topiroxostat for Hyperuricaemic patients with overt diabetic nephropathy study (ETUDE study): A prospective, randomized, multicentre clinical trial

“…It was speculated that urinary L‐FABP increased with ROS, which was generated with activation of XO in renal tubule due to a decrease in mitochondrial ATP production function, promotion of ATP catabolism and increase hypoxanthine. In adenine‐induced renal injury model mice, topiroxostat treatment attenuated tubulointerstitial damage while decreasing albuminuria and avoiding increases in serum creatinine level . They also showed that mice treated with high doses of topiroxostat (3 mg/kg) had lower serum creatinine, urinary L‐FABP, and renal XOR than the mice group treated with febuxostat (3 mg/kg) .…”